Reprinted from the ∙ German Journal of Psychiatry ∙ http:/www.gwdg.

de/~bbandel ∙ ISSN 1433-1055

Cardiovascular changes in alcoholic patients

during withdrawal phase
1 2
Seppo Kähkönen and Boris B. Bondarenko
1
BioMag Laboratory, Medical Engineering Center, Helsinki University Central Hospital, Helsinki
and Cognitive Brain Research Unit, University of Helsinki, Finland
2
Cardiology Research Institute, St. Petersburg, Russia

Corresponding author: Seppo Kähkönen, M.D, Ph.D., BioMag Laboratory, Helsinki University
Central Hospital, P. O. Box 442, FIN-00290 Helsinki, Finland; Seppo.Kahkonen@helsinki.fi

Abstract
Background: Haemodynamic changes such as tachycardia, arterial hypertension and elevated cardiac output are
usual in alcohol withdrawal syndrome (AWS). Objective: We investigated central haemodynamics in alcoholic
patients non-invasively in different phases of AWS parallel to recording AWS symptoms. Material and methods:
22 alcoholic patients during different phases of withdrawal were investigated 1, 2, 3 and 10 days after
admission for detoxification. The intensity of alcohol withdrawal syndrome (AWS) was evaluated with a rating
scale. Stroke volume (SV) was measured with an impedance cardiogram, systolic (SBP), diastolic (DBP), and
mean blood pressures (MBP) were measured with a sphygmomanometer by Korotkoff, and heart rate (HR) was
obtained from an electrocardiogram (ECG). Cardiac output (CO) and total peripheral resistance (TPR) were
calculated. Results: The intensity of AWS decreased towards Day 10. Concomitantly, MBP decreased which
was attributable to a reduction of both SBP and DBP. Changes in TPR were proportional to the level of change
in SV. The level of HR measured on Day 10 differed from the HR on Day 1 but not from rates on Days 2 and
3. The CO tended to be maintained at the same level during AWS. Depending on the level of CO on Day 1,
the haemodynamic parameters underwent different courses towards the end of AWS. When CO was low (<6 l),
TPR decreased and CO tended to be at the same level. The opposite was true when CO was high (> 6 l).
Conclusion: These results suggest that the adaptive capacity of haemodynamics appears to be preserved in
patients with alcohol withdrawal without evident cardiac diseases. The cardiovascular system of alcoholic
patients tends to adapt to the changing level of activity in the sympathetic nervous system during alcohol
withdrawal (German J Psychiatry 2000;3:1-6).

Key words: alcoholism, cardiac output, blood pressure, heart rate, haemodynamics, impedance cardiography,
substance withdrawal syndrome

diastolic blood pressures (DBP) as well as accelerated

Introduction heart rate (HR) often follow AWS. Even a single
moderate dose of alcohol ingestion in non-alcoholic

A
lcohol withdrawal syndrome (AWS) is subjects causes significant changes in haemodynamics.
characterised by increased anxiety, During the phase of rising blood ethanol, HR and
tremulousness, paroxysmal sweating and cardiac output (CO) increase and total peripheral
reduced sleep, which develop after cessation of alcohol resistance (TPR) decreases. In contrast, during the
abuse (Gross et al., 1974, Koch-Weser et al., 1976). declining blood ethanol phase, SBP and stroke volume
Cardiovascular changes as increased systolic (SBP) and (SV) decrease (Kupari, 1983).
 KÄHKÖNEN & BONDARENKO
Pronounced haemodynamic changes are usual in AWS:
tachycardia, arterial hypertension and elevated cardiac
output (Carlsson, 1971; Beckman et al., 1981; Saunders
et al., 1981; Clark and Friedman, 1985). Alcohol abuse
and hypertension are strongly associated, with a 50 to
150% higher prevalence in heavy users of alcohol than
in abstainers (Clark, 1984; Beevers and Maheswaran,
1988). Alcoholics admitted for detoxification frequently
have blood pressure exceeding 140/90 mmHg. In most
cases, this appears as a transitory hypertension, with
pressures returning to normal a few days after acute
withdrawal. If abstinence continues, these alcoholics will
usually remain normotensive at rest (Saunders et al.,
1981; Clark and Friedman, 1985). However, in some
alcoholic subjects the BP elevation during AWS may
predict future BP abnormalities (King et al., 1991). The
degree of hypertension seen during AWS closely
correlates with AWS severity (Potter et al., 1984) and
with the amount of alcohol taken during the most
recent hard-drinking period (Clark and Friedman,
1985). A transient increase occurs in SBP, but not in
DBP during AWS, which decreases with the resolution
of the withdrawal symptoms. The degree of change is
markedly affected by age. Younger patients have a greatly
accentuated lability as compared to the older age-group
(Beckman et al., 1981). King et al. (1996) have reported
cardiodynamic changes at 3-4 weeks postwithdrawal in
alcoholic patients with transitory hypertension during
withdrawal. Elevated peripheral resistance, elevated
heart rate, and reduced stroke volume were observed
during rest and an isometric handgrip task.
Orthostatic hypotension may occur in AWS as a result
of impaired blood-pressure control. Thus, Eisenhofer et
al. (1985) reported that despite a raised plasma
concentration of catecholamines and HR responses to
standing, withdrawing alcoholics as a group showed a
fall in BP on standing, four out of ten patients having a
fall of more than 30/5 mmHg. De Marchi et al. (1986)
were unable to confirm these findings; only a small
percentage (3.5%) exhibited mild to severe orthostatic
hypotension, whereas a significant percentage (56%) of
withdrawing alcoholics showed an increase in BP in a
standing position.
In this study we investigated central haemodynamics in
alcoholic patients non-invasively in different phases of
AWS parallel to recording AWS symptoms.
2
Subjects and Methods
Patients. 22 patients with alcohol dependence in AWS
were investigated within 1, 2, 3, and 10 days of
admission to an alcohol in-patient unit for
detoxification. All fulfilled the DSM-III-R criteria for
alcohol dependence and alcohol withdrawal (American
Psychiatric Association, 1987). Patients with other
psychiatric pathology and substance-abuse, complicated
forms of AWS, and alcoholism, as well as evident
cardiologic diseases were excluded. All were males under
50 years of age.
The patients underwent a routine clinical and
psychiatric examination. Relevant laboratory tests
commonly used to evaluate liver and kidney functions
(ASAT, ALAT and urea), a blood and urine
examination, and an electrocardiogram (ECG) were
included. Withdrawal symptoms were treated with oral
diazepam 10-20 mg per day as needed. Diazepam was
not given at least three days prior to the first
examination or three days prior to the examination on
Day 10. The characteristics of patients are summarized
in Table 1. Informed written consent and institutional
approval were obtained.
Table 1. Sample characteristics
Characteristic Mean ± SEM
Age (yr) 37 ± 1.4
Duration of heavy drinking (yr) 12 ± 1.3
Duration of AWS (yr) 8 ± 1.4
Daily ethanol consumption (g) 351 ± 18
Duration of last alcohol abuse (days) 19 ± 4.1
Rating the alcoholic symptoms. The structure and
severity of AWS were studied with the aid of a rating
scale, which includes a list of general WS manifestations,
viz. alcohol craving, depressed mood, anxiety,
suspiciousness, irritability, transient hallucinations or
illusions, weakness, insomnia, headache, tremor,
polyuria, vomiting, anorexia, diarrhea, thirst, chest pain,
tachycardia, elevated blood pressure and hyperemia. The
intensity of each symptom was scored as follows: 2 (=
symptom present and marked), 1 (= all other types of
symptoms present) or 0 (=symptom is absent). The
recording of symptoms in accordance with the rating
scale was done on Days 1, 2, 3 and 10 of admission to
the hospital, at approximately the same time of the day.
Haemodynamic measurements. Cardiodynamic
variables were measured by an impedance cardiograph
system (RPG 2-02, Russia) using four band-electrodes as
described by Kubicek et al. (1966). Two aluminium band
Table 2. Central haemodynamic changes in AWS

Day HR SBP DBP MBP SV CO TPR AWS

1 85±4.2 141±4.0 91±2.4 106±2.6 71±8.1 5.8±0.5 1790±168 17±1.0
2 79±3.5 133±3.8 87±2.5 101±2.7 62±4.9 4.8±0.3 1900±164 11±1.1
3 77±2.7 129±3.6 86±3.0 99±3.0 67±5.1 5.1±0.4 1760±136 7.5±0.7
10 72±2.3 119±2.7 79±1.5 92±1.6 83±6.2 5.7±0.4 1410±101 1±0.4
ANOVA F 5.25 17.81 10.80 12.43 4.76 2.08 3.39 102.85
p <0.01 <0.001 <0.001 <0.001 <0.01 NS <0.05 <0.001
p1-10 Days <0.01 <0.001 <0.001 <0.001 NS NS NS <0.001
p2-10 Days NS <0.01 <0.001 =0.001 <0.001 NS >0.001 <0.001
p3-10 Days NS <0.01 <0.01 <0.01 =0.02 NS =0.02 <0.001
Abbrevations: AWS= alcohol withdrawal syndromes (scores); HR= heart rate beat/min); SBP, DBP and MBP= systolic,
diastolic and mean blood pressure (mmHg); SV= stroke volume (ml); CO= cardiac output (l/min); TPR= total peripheral
resistance (dyne ×s ×cm )
-5

electrodes, separated as widely as possible, were placed
around the neck of the subject. A third electrode band
was placed around the thorax just below the xiphoid
process, and a fourth electrode about 5 cm below the
third one. The outer electrodes were provided with a
constant sinusoidal current (4 mA) with a frequency of
100 kHz. The potential changes, which reflect the
changes in the impedance between the two inner
electrodes, were picked up. The parameters of
impedance cardiography were measured with the patient
in a supine position after a 10-minute rest separately in
the state of unforced breathing, of inspiration, and of
expiration (at least 10 epochs for each), and the mean
value was taken. Impedance cardiography has been
reported to be a reliable method for measuring relative
changes in SV and CO (Pushar et al, 1977; Sherwood et
al., 1990, Fuller, 1992)
The following parameters were measured or calculated
as follows:
(1) SBP and DBP (mmHg) measured with
sphygmomanometer by Korotkoff. MBP (mm
Hg) calculated from the formula MBP = (SBP +
2 x DBP)/3
(2) HR (beat/min) from the ECG
(3) SV (ml) of the heart by impedance cardiography
utilizing the formula of Kubicek-Gundarov
(Kubicek et al., 1966; Gundarov et al., 1983)
(4) CO (l/min) refers to HR x SV
(5) TPR (dyne?s/cm-5) calculated from the formula
TPR = MBP/CO
Statistics. Results were expressed as the mean ± SEM
values. A one-way ANOVA for repeated measures was
used for analyzing differences of haemodynamic
parameters between days. Pairwise comparisons between
groups were performed using a paired t-test. In these cases a
Bonferroni correction was used to protect against type I
errors. Correlation coefficients (r) were calculated by the
Spearman rank test.
Results
It appears that significant overall changes occurred in all
haemodynamic parameters studied during AWS, except
for CO. The severity of AWS gradually declined towards
the end of AWS, and MBP decreased concomitantly
with declining AWS. This decrease in MBP was
attributable to a reduction of both SBP and DBP.
Changes in TPR were proportional to the level of
change in SV. The level of HR measured on Day 10
differed from the HR on Day 1 but not from rates on
Days 2 and 3. The CO tended to be maintained at the
same level during AWS.
The severity of AWS on Day 1 correlated positively with
the duration of recent alcohol abuse (r=0.44, p<0.05),
with heavy ingestion of alcohol (r=0.56, p<0.01), and
with duration of withdrawal syndrome (r=0.60,
p<0.001). SBP on Day 1 correlated positively with the
severity of AWS (r=0.46, p<0.05). SV and CO correlated
positively with daily consumption of alcohol (r=0.52,
p<0.05 and r=0.47, p<0.05, respectively). No significant
correlations were found between anamnestic
characteristics and HR, DBP and TPR on Day 1.
Table 3 shows that an equal decrease in MBP by Day 10
can be associated with differing CO and TPR changes.
Thus, in patients with initially low CO, the TPR
decreased significantly (t = 2.35; p<0.05), whereas CO
did not increase (t = 0.78; p>0.05) by Day 10. In patients
with initially high CO, a significant decrease in CO (t =
2.52; p<0.05) occurred, whereas TPR did not increase (t
= 1.34; p>0.05). In the first group of patients, lowered
MBP led to decreased TPR which was compensated for
by increased CO. In the second category of patients,
lowered MBP was due to decreased CO.

3
 KÄHKÖNEN & BONDARENKO

Table 3. Changes in haemodynamics with different levels of CO on Day 1 antidiuretic hormone may induce
the pressor effect of angiotensin II
Group MBP HR CO TPR
A Initial 112±3.5 89±5.8 4.2±0.3 2200±183
and catecholamines and enhance
A Change -16±2.4 -18±4.7 0.8±0.6
**
-540±268
* the discharge of ACTH (Potter et
B Initial 109±5.9 81±8.2 8.5±0.7 1080±131 al., 1984). In contrast to this,
B Change -13±3.5 -14±8.3 -1.4±0.5 29±99
Arkwright et al. (1982) reported
Patients in group A (n=14) showed low CO (<6 l/min) on Day 1; group B (n=8)
* **
showed high CO (>6 l/min) on Day 1. p<0.05, p<0.01 in comparison with group that hypertensive alcoholics have
B change values. Abbrevations: HR in beats/min; MBP in mmHg; CO in l/min; normal plasma concentrations of
TPR in dyne ×s ×cm .
-5
cateholamines, angiotensin and
aldosterone. There is a reversible decrease in renal
Discussion sodium excretion which closely correlates with the BP
level (De Marchi and Cecchin, 1985).
The results confirm the complex structure of alcohol It is also possible that the direct action of ethanol on the
AWS, the evolution of which is characterized by a rapid vascular wall is responsible for elevated BP in AWS.
decline in intensity of WS, including the changes in the Vasoconstriction occurring in AWS is believed to be one
cardiovascular system. Our results showed that the of the mechanisms active in the development of the
adaptive capacity of the cardiovascular system in brain insults seen in alcoholic patients (Altura et al.,
alcoholic patients during AWS is preserved. During 1983). However, these effects are not identical for all
AWS, cardiac output tended to be maintained at the vascular beds. Ethanol depresses the normal spontane-
same level. The finding that haemodynamic alterations ous activity of small arteries and veins and inhibits their
paralleled changes in AWS severity may suggest that contractile responses to the endogenous neurohumoral
these changes during AWS are due mainly to substances, thus causing vasodilation (Altura and Altura,
extracardial effects. The severity of AWS also depends 1982). The direct action of ethanol on the vascular wall
on anamnestic data, such as daily consumption of makes it more sensitive to the effects of other vasoactive
ethanol, and duration of recent alcohol abuse, and substances. However, it remains unclear why the alco-
duration of withdrawal syndrome. Mechanisms of holic patient with a high blood ethanol level often has
lowered MBP differ in AWS, depending on the initial normal BP which becomes hypertensive during AWS
haemodynamic indices at the onset of AWS. (Saunders et al., 1981). Impairment of the baroreceptor
Correlation analysis of haemodynamic parameters (SBP, reflex has been observed in alcohol-treated rats (Abdel-
SV, CO) in alcoholic patients on Day 1 demonstrates Rahman et al., 1985), but Rhee et al. (1989) could not
that their level depends on the severity of AWS and on confirm this finding. Autonomic nervous damage may
heavy ingestion of alcohol. An increase in SBP as well as in part contribute to withdrawal hypertension (Yoko-
AWS severity may reflect the degree of activation of the yama et al., 1991; Murata et al., 1994; Miralles et al.,
sympathoadrenal system (Hawley et al., 1985). As the 1995). In alcoholic patients, interaction between so-
alcoholism progresses, there is a risk of toxic myocardiac dium, magnesium, and calcium ions has been described
damage and impairment of the heart's contractile as playing a role in the genesis of hypertension (Adeniyi,
function (Wu et al., 1976). 1986).
The exact mechanism of haemodynamic alterations in A hyperdynamic circulatory state is often seen in alco-
alcohol withdrawal has not been fully elucidated, but it holic patients undergoing withdrawal, and during delir-
appears to be complex and may involve central and ium tremens in particular (Mendelson, 1970; Abraham
peripheral systems regulating haemodynamics. The et al., 1985). Ballas et al. (1982) showed that the SV was
important role of endogenous active substances not significantly different from normal values, but some
determining haemodynamic changes is not excluded, of the patients during AWS exhibit decreased SVs not
the hormones of the hypothalamus-hypophysis-adrenal due to any heart diseases. However, the material of that
cortex axis playing the major role. Thus, the cortisol study included patients without severe forms of AWS,
concentration increases and correlates positively with and haemodynamic control values were not obtained
the BP level (Smals et al., 1976; Bannan et al., 1984; after AWS developing. Beta-adreno receptor blockers
Potter et al., 1984). The increase in cortisol level may be timolol and propranolol tended to normalize elevated
caused by stimulation (Gilles et al., 1982) directly or via HR and CO, and to correct high TPR (Carlsson, 1971;
the secretion of antidiuretic hormone which becomes Potter et al., 1984), showing that central and peripheral
greater in AWS (Jenkins and Connolly, 1968). This beta-adrenoreceptors may regulate withdrawal-induced
haemodynamic changes in alcoholic patients.

4
In summary, significant changes were observed in
haemodynamics of alcoholic patients during withdrawal,
paralleling a decrease in the severity of withdrawal symp-
toms. The adaptive capacity of haemodynamics appears
to be preserved in patients with alcohol withdrawal
without evident cardiac diseases. The cardiovascular sys-
tem tends to adapt to the changing level of activity in the
sympathetic nervous system in the alcohol withdrawal
state.
References
Abdel-Rahman A-RA, Dar MS, Wooles WR: Effect of chronic
ethanol administration on arterial baroreceptor
function and pressor and repressor responsiveness in
rats. J Pharmacol Exp Ther 232; 194-201: 1985
Abraham E, Shoemaker WS, McCartney SF. Cardiorespiratory
patterns in severe delirium tremens. Arch Intern Med
145; 1057-1059: 1985
Adeniyi FA. Interactive roles of monovalent and divalent
cations in pathogenesis of hypertension caused by
alcohol. J Clin Pathol 39; 1264-1268: 1986
Altura BM, Altura BT, Gergebrevol DA. Alcohol induced
spasms of cerebral blood vessels in relation to
cerebrovascular accident and sudden death. Science
220; 331-333: 1983
American Psychiatric Association: Diagnostic and Statistical
Manual of Mental Disorders, Third Edition, Revised,
Washington, DC, American Psychiatric Association,
1987
Arkwright PD, Beilin LJ, Rouse L, Vandongen R. The pressor
effect of moderate alcohol consumption in man: a
search for mechanism. Circulation 66; 515-519: 1982
Ballas M, Zoneraich S, Yunis M, Zoneraich O, Rosner F.
Noninvasive cardiac evaluation in chronic alcoholic
patients with alcohol withdrawal syndrome. Chest 82;
148-153; 1982
Balldin J, Berggren U, Engel J, Lindstedt G, Sundkler A,
Wålinder J: Alpha-2-adrenoceptor sensitivity in early
alcohol withdrawal. Biol Psychiatry 31; 712-719: 1992
Bannan LT, Potter JP, Beevers DG, Saunders JB, Walterns
JRF, Ingram MC. Effect of alcohol withdrawal on
blood pressure, plasma renin activity, aldosterone,
cortisol and dopamine-hydroxylase. Clin Science 66;
659-663: 1984
Beckman H, Frank RR, Robertson RD, Brady KA, Coin EJ.
Evaluation of blood pressure during early alcohol
withdrawal. Ann Emerg Med 10; 32-35: 1981
Beevers DG, Maheswaran R. Does alcohol cause hypertension
or pseudo-hypertension? Proc Nutr Soc 47; 111-114:
1988
Carlsson C. Haemodynamic studies in alcoholics in the
withdrawal phase. Int J Clin Pharmacol Ther Toxicol 3;
61-63: 1971
Clark LT. Alcohol use and hypertension: clinical
considerations and implications. Postgrad Med J 75;
273-276: 1984
Clark LT, Friedman HS. Hypertension associated with alcohol
withdrawal: Assessment of mechanisms and
complications. Alcoholism: Clin Exper Res 9; 125-130:
1985
De Marchi S, Cecchin E. Alcohol withdrawal and
hypertension: evidence for a kidney abnormality. Clin
Science 69; 239-240: 1985
De Marchi S, Cecchin E. Are orthostatic hypotension and
impaired blood pressure control common features of
alcohol withdrawal syndrome? Clin Science 70; 213-
214: 1986
Eisenhofer G, Whiteside EA, Johnsson RH. Plasma
catecholamine responses to change of posture in
alcoholics during withdrawal and after continued
abstinence from alcohol. Clin Science 68; 71-78: 1985
Eisenhofer G, Szabo G, Hoffman PL: Opposite changes in
turnover of noradrenaline and dopamine in the CNS
of ethanol-dependent mice. Neuropharmacology 29;
37-45: 1990
Fuller HG. The validy of cardiac measurement by thoracic
impedance: a meta-analysis. Clin Invest Med 15; 103-
112: 1992
Gilles GH, Linton EA, Lowry PL. Corticotropin releasing
activity of the new CRF is potentiated several times by
vasopressin. Nature 299; 355-357: 1982
Gross MM, Lewis E, Hastey J. Acute alcohol withdrawal
syndrome. In: Biology of alcoholism. Vol 3. Clinical
Pathology. New York, Plenum Press, pp 191-263, 1974
Gundarov IA, Pushkar YT, Konstantinov YI. The central
haemodynamic norms determined by impedance
cardiography. Ther Arch 55; 26-28: 1983
Jenkins JS, Connolly J. Adrenocortical response to ethanol in
man. Br Med J 2; 804-805: 1968
King AC, Errico AL, Parsons OA. Blood pressure
dysregulation associated with alcohol withdrawal.
Alcohol Clin Exp Res 15; 478-482: 1991
King AC, Bernardy NC, Parsons OA, Lovallo WR.
Hemodynamic alterations in alcohol-related transitory
hypertension. Alcohol 13; 387-393: 1996
Koch-Weser J, Sellers EM, Kalant H. Alcohol intoxication and
withdrawal. N Engl J Med 294; 757-762: 1976
Kubicek WG, Karnegis JN, Patterson RP, Witsoe DA, Mattson
RH. Development and evaluation of an impedance
cardiac output system. Aerospace Med 37; 1208-1212:
1966
Kupari M: Acute cardiovascular effects of ethanol. A
controlled non-invasive study. Br Heart J 49;174-82:
1983
Mendelson JH, Ogata M, Mello NK. Adrenal function and
alcoholism. I. Serum cortisol. Psychosom Med 33; 145-
57: 1971
Miralles R, Espadaler JM, Navarro X, Rubies-Prat J. Auto-
nomic neuropathy in chronic alcoholism: evaluation
of cardiovascular, pupillary and sympathetic skin re-
sponses. Eur Neurology 35; 287-292: 1995
5
 KÄHKÖNEN & BONDARENKO

Murata K, Araki S, Yokoyama K, Sata F, Yamashita K, Ono

Y. Autonomic neurotoxicity of alcohol assessed by
heart rate variability. J Autonomic Nervous System
48; 105-111: 1994
Potter JF, Bannan LT, Beevers DG. Alcohol and hypertension.
Br J Addiction 79; 365-373: 1984
Pushkar YT, Bolshov VM, Yelisarova NA. Determination of
the cardiac output by impedance cardiography.
Cardiology 17; 85-90: 1977
Rhee HM, Valentine JL, Hendrix D, Schweisthal M, Soria M.
Hemodynamic responses to vasoactive compounds in
chronically alcohol treated rats. Adv Exp Med Biol 248;
629-639: 1989
Saunders JB, Bevers BC, Paton A. Alcohol induced
hypertension. Lancet 2; 653-656: 1981
Sherwood A, Allen MT, Fahrenberg J, Kelsey RM, Lovallo
WR, van Doornen LJP. Methodological guidelines for
impedance cardiography. Psychophysiology 27; 1-23:
1990
Smals AG, Kloppenberg PW, Njo T, Knoben JN, Ruland CM.
Alcohol-induced Cushingoid syndrome. Br Med J 2;
1298-1299: 1976
Yokoyama A, Takagi T, Ishii H. Impaired autonomic nervous
system in alcoholics assessed by heart rate variation.
Alcohol Clin Exp Res 15; 761-765: 1991
Wu CF, Sudhaker M, Ghazanfar J, Ahmed SS, Regan TJ.
Preclinical cardiomyopathy in chronic alcoholics: a sex
difference. Am Heart J 91; 281-6: 1976

The German Journal of Psychiatry ∙ ISSN 1433-1055 ∙ http:/www.gwdg.de/~bbandel

Editor-in-Chief: PD Dr. Borwin Bandelow, Dept. of Psychiatry, The University of Göttingen, von-Siebold-Str. 5, D-
37075 Germany; tel. ++49-551-396607; fax: ++49-551-392004; e-mail: bbandel@gwdg.de